Human papillomavirus (HPV) infection is the most common viral sexually transmitted infection (STI), and infection with high-risk types of HPV (16, 18, and others) has been implicated in the majority of anogenital malignancies. HIV-infected women are at higher risk for HPV infection, persistent HPV infection, cervical abnormalities, and cervical cancer. Although many HIV+ women are infected with HPV, even in this immune suppressed population, relatively few women progress to cervical abnormalities, indicating that HPV infection is necessary but not sufficient for development of cervical cancer. Thus, other co-factors must augment the oncogenic potential of HPV. The known oncogenic virus, Epstein-Barr virus (EBV), is shed from the cervix, making this a prime co-factor candidate for HPV-related cervical dysplasia. Preliminary data show that HIV+ women from New Orleans (n=531) or from a pilot study of the WIHS cohort (n=308) with detectable cervical HPV and EBV are at higher risk (68%) for concurrent squamous intraepithelial lesions (SIL) as compared to only 45% of women with only detectable HPV. In addition, cervical abnormalities in co-shedding HIV+ women are more likely to progress. The cervical shedding of EBV, the potential of this virus to cause human malignancy, and our preliminary data have led us to hypothesize that EBV acts as a co-factor in the development and progression of HPV-induced cervical abnormalities in HIV+ women. From this hypothesis, it is predicted that (1) the risk factors for the cervical co-shedding of EBV and HPV and dysplasia will be the same (epidemiological relationship); (2) EBV and HPV will be shed prior to the development of dysplasia and be persistent in women who progress to higher grade lesions (temporal relationship); (3) these two oncoviruses will be located to facilitate interactions (spatial relationship); and (4) EBV and HPV will infect the cervical epithelial cells and interact directly or indirectly (functional relationship). It is also predicted that this EBV-HPV interaction will also be seen in high-risk HIV-negative women. The four specific aims will test these predictions and provide initial insights into the mechanism of interaction between these two oncoviruses: 1. Determine the risk factors for co-shedding of EBV and high oncogenic risk HPV in HIV+ and high- risk HIV-negative women. 2. Determine the temporal relationship between EBV and HPV in the development of cervical dysplasia in HIV+ and high-risk HIV-negative women. 3. Determine the spatial relationship between EBV and HPV in the development of cervical dysplasia in HIV+ and high-risk HIV-negative women. 4. Initial determination of the functional relationship between EBV and HPV in the development of cervical dysplasia. These studies will better define the interaction of EBV with HPV in the development of cervical dysplasia and will provide the initial understanding of the mechanism of this interaction. This could lead to improved methods to prevent cervical cancer, especially for HIV+ women. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: Human papillomavirus is the cause of most cases of cervical cancer; however, most women infected with this virus do not progress to pre-cancer or cancerous, lesions implying the need for co-factors in this process. Accumulated evidence points to another cancer-causing virus, Epstein-Barr virus, (EBV), as the potential co- factor, particularly in those women also infected by the HIV virus. This proposal is to further explore the role of EBV in the development HPV-related cervical cancer. [unreadable] [unreadable] [unreadable]